MD3866767T2 - Pharmaceutical composition for oral administration comprising aminopyrimidine derivative or its salt - Google Patents

Abstract

The present disclosure provides a pharmaceutical composition for oral administration comprising: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4- methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

Description

Cross reference to related applications

This patent application claims priority to Korean patent application no. 10-2018-0124171, filed on October 18, 2018.

The technical field

The present disclosure relates to a pharmaceutical composition for oral administration comprising an aminopyrimidine derivative or its salt. More particularly, the present disclosure relates to a pharmaceutical composition comprising N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4 -methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or its salt and a combination of microcrystalline cellulose and mannitol as a diluent.

Background

WO 2016/060443 discloses an aminopyrimidine derivative, for example, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)- 4-Methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or its pharmaceutically acceptable salt. Lazertinib or its pharmaceutically acceptable salt has selective protein kinase inhibitory activity, especially protein kinase for a mutant epidermal growth factor receptor, and may provide, for example, an effective and safe method of treatment for non-small cell lung cancer. Lazertinib or its pharmaceutically acceptable salt has been known as an irreversible EGFR TKI, which has less effect on wild-type EGFR, strong inhibitory activity on active single mutation T790M (EGFRm) and double mutation, and excellent selectivity, and is expected to exhibit an effective therapeutic effect in the treatment of patients with primary cancer of progressive non-small cell lung cancer and progressive non-small cell lung cancer accompanied by brain metastasis.

When Lazertinib or its salt is formulated as a composition for oral administration, consideration may be given to formulating Lazertinib or its salt as an immediate release pharmaceutical composition having a mechanism in which the active ingredient is released immediately in the stomach and then transferred to the intestine thin to be absorbed. In formulating such an immediate release pharmaceutical composition, it is necessary to minimize the effect of pH changes in the stomach, for example, in accordance with food or drugs administered simultaneously (eg, an antacid, etc.). For example, since the pH in an empty stomach is not constant, ranging from pH 1 to pH 3.5, and also an average pH in a postprandial stomach is pH 4 (pH 3 to 5), there may be deviations in the dissolution rate depending on the physico-chemical properties of an active ingredient, which can lead to changes in the absorption rate and bioavailability.

Summary

The present inventors have discovered that when N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2- morpholinophenyl)acrylamide (Lazertinib) or its salt are formulated using a combination of specific diluents, it is possible to prepare an immediate release pharmaceutical composition capable of minimizing the effect according to changes in the pH environment of the stomach. In addition, the present inventors have discovered that the pharmaceutical composition can be formulated to provide excellent stability and exhibit significantly increased bioavailability.

Therefore, an object of the present disclosure is to provide a pharmaceutical composition for oral administration of Lazertinib or a pharmaceutically acceptable salt thereof comprising a combination of specific diluents.

In accordance with one aspect of the present disclosure, there is provided a pharmaceutical composition for oral administration comprising N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin- 2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

In the pharmaceutical composition of the present disclosure, a mass ratio of microcrystalline cellulose to mannitol may be in the range of 1:0.9 to 1:3 and preferably 1:0.9 to 1:1.5.

The pharmaceutical composition of the present disclosure may further include croscarmellose sodium as a disintegrant, and croscarmellose sodium may be present in a range of 0.5 to 10% by mass, preferably 2 to 5% by mass, of the total mass of the composition. In addition, the pharmaceutical composition of the present disclosure may further include magnesium stearate as a lubricant. In one embodiment, the pharmaceutical composition of the present disclosure includes N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4- methoxy-2-morpholinophenyl)acrylamide or its pharmaceutically acceptable salt as an active ingredient; a combination of microcrystalline cellulose and mannitol as a diluent; croscarmellose sodium as a disintegrating agent; and magnesium stearate as a lubricant.

In the pharmaceutical composition of the present disclosure, the active ingredient may be mesylated by N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)- 4-Methoxy-2-morpholinophenyl)acrylamide.

In one embodiment, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2- morpholinophenyl)acrylamide can be a crystalline form having a PXRD pattern with maxima at 5.614, 12.394, 14.086, 17.143, 18.020, 19.104, 21.585, 22.131, and 22.487°2θ ± 0.2°2θ. In another embodiment, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2 -morpholinophenyl)acrylamide may be a crystalline form having a differential scanning calorimetric (DSC) thermogram with an endothermic maximum of 210 to 230°C, preferably 217±2°C.

In accordance with the present disclosure, it has been found that when N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4- methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or its salt are formulated using a combination of specific diluents, i.e., a combination of microcrystalline cellulose and mannitol, it is possible to prepare an immediate release pharmaceutical composition capable of minimizing the effect according to changes in the pH environment in the stomach. In addition, the pharmaceutical composition of the present disclosure can be formulated to provide excellent stability and achieve significantly increased bioavailability.

Brief description of the drawings

FIG. 1 is a powder X-ray diffractometry (PXRD) plot of Lazertinib mesylate prepared in Reference Example 1.

FIG. 2 is a differential scanning calorimetric (DSC) plot of Lazertinib mesylate prepared in Reference Example 1.

FIG. 3 is a photograph illustrating the results of the stability test performed under stress conditions with respect to Lazertinib mesylate prepared in Reference Example 1 (Initial: at the start, 2 weeks: after 2 weeks, 4 weeks: after 4 weeks).

FIG. 4 is a photograph illustrating the results of the stability test performed under accelerated conditions with respect to the Lazertinib mesylate prepared in Reference Example 1 (Initial: at the start, 1 month: after 1 month, 3 months: after 3 months, 6 months: after 6 months).

FIG. 5 illustrates the comparative pharmacokinetic test results for Lazertinib mesylate and Lazertinib free base, which are performed in normal rats.

FIG. 6 illustrates the comparative pharmacokinetic test results for Lazertinib mesylate and Lazertinib free base, which are performed in rats treated with esomeprazole.

FIG. 7 illustrates the comparative pharmacokinetic test results for Lazertinib mesylate and Lazertinib free base, which are performed on beagle dogs.

FIG. 8 illustrates the results obtained by performing dissolution tests under a pH 1.2 condition against the tablet (Example 5) obtained in accordance with the present disclosure and the tablet of Comparative Example (Comparative Example 1).

FIG. 9 illustrates the results obtained by performing dissolution tests under a pH 4.0 condition against the tablet (Example 5) obtained in accordance with the present disclosure and the tablet of Comparative Example (Comparative Example 1).

FIG. 10 illustrates an enlarged result of the dissolution tests of FIG. 9.

FIG. 11 illustrates the results obtained by performing dissolution tests under a condition of pH 4.0 against tablets (Examples 1 and 2) obtained in accordance with the present disclosure and the tablet of Comparative Example (Comparative Example 3).

FIG. 12 illustrates the results obtained by performing dissolution tests under continuous conditions of an acid phase (pH 1.0) and a buffer phase (pH 6.8) against the tablet (Example 7) obtained according to the present disclosure and the tablets of the Comparative Examples (Comparative examples 5 and 6).

FIG. 13 illustrates a blood concentration profile obtained by performing a pharmacokinetic test against the tablet (Example 7) obtained in accordance with the present disclosure and the tablet of Comparative Example (Comparative Example 2).

Detailed description of exemplary achievements

The present disclosure provides a pharmaceutical composition for oral administration comprising N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy -2-morpholinophenyl)acrylamide (Lazertinib) or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

In this specification, 'diluent' and 'additive' have the same meaning and may be used interchangeably. In accordance with the present disclosure, it has been discovered that when Lazertinib or its salt is formulated using a combination of specific diluents, i.e., a combination of microcrystalline cellulose and mannitol, it is possible to prepare an immediate release pharmaceutical composition capable of minimizing the effect in according to changes in the pH environment in the stomach. Changes in the pH environment of the stomach include a change in pH by diet; and a change in pH by drugs, for example, but not limited to, a proton pump inhibitor such as esomeprazole or an H2 receptor antagonist such as cimetidine, an antacid, and the like.

In the pharmaceutical composition of the present disclosure, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2- morpholinophenyl)acrylamide (Lazertinib) or its pharmaceutically acceptable salt can be used in therapeutically effective amounts. For example, Lazertinib or a pharmaceutically acceptable salt thereof can be used in a range of 10 to 320 mg as Lazertinib per unit formulation (eg, per unit tablet), and can be used in amounts of, for example, 10 mg , 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 160 mg, 240 mg, or 320 mg.

The pharmaceutical composition of the present disclosure includes a combination of specific diluents, ie, a combination of microcrystalline cellulose and mannitol. According to the present disclosure, it has been found that when the mass ratio of mannitol to microcrystalline cellulose is 0.5 times to three times, Lazertinib or its salt can minimize the effect according to changes in the stomach pH environment. Accordingly, the mass ratio of microcrystalline cellulose to mannitol may preferably be in a range of from 1:0.5 to 1:3, more preferably from 1:0.9 to 1:3, more preferably from 1:0.9 to 1:1.5, and particularly preferably from about 1:0.95 to 1:1.2.

The pharmaceutical composition of the present disclosure may include a disintegrating agent and/or a lubricant (or a rheological agent), in addition to the diluent.

The disintegrating agent may be a conventional disintegrating agent used in the pharmaceutical field. However, according to the present disclosure, it has been found that when using a specific disintegrating agent, i.e., croscarmellose sodium among various disintegrating agents, precipitation is significantly delayed when the disintegrated/dissolved drug in the stomach is transferred to the intestine. Accordingly, it is preferred that the pharmaceutical composition of the present disclosure include croscarmellose sodium as a disintegrating agent. Croscarmellose sodium may be present, for example, in a range of 0.5 to 10% by weight, preferably 2 to 5% by weight, relative to the total weight of the composition.

The lubricant (or rheological agent) can be a conventional lubricant used in the pharmaceutical field. However, according to the present disclosure, it has been found that a specific lubricant, which is magnesium stearate, among various lubricants, has particularly excellent compatibility with Lazertinib or its salt, thereby providing excellent stability. Accordingly, it is preferred that the pharmaceutical composition of the present disclosure include magnesium stearate as a lubricant (or rheological agent). Magnesium stearate may be used in an amount sufficient to obtain a sufficient lubricating effect, and for example, may be present in a range of 0.4 to 2% by weight, based on the total weight of the composition, but is not limited to this.

In one embodiment, the pharmaceutical composition of the present disclosure includes N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4- methoxy-2-morpholinophenyl)acrylamide or its pharmaceutically acceptable salt as an active ingredient; a combination of microcrystalline cellulose and mannitol as a diluent; croscarmellose sodium as a disintegrating agent; and magnesium stearate as a lubricant.

Lazertinib mesylate has been found to be excellent in stability, solubility, and bioavailability compared to the free base compound and can be prepared with high purity. In addition, it has been found that there is an advantage that Lazertinib mesylate has excellent bioavailability even when co-administered with, for example, an antacid, as well as when administered alone. Accordingly, in the pharmaceutical composition of the present disclosure, the active ingredient may be Lazertinib mesylate. In one embodiment, the pharmaceutical composition of the present disclosure may consist of 5 to 54% by weight of Lazertinib mesylate; 45 to 87% by weight of a combination of microcrystalline cellulose and mannitol; 0.5 to 10% by mass of croscarmellose sodium; and 0.4 to 2% by weight of magnesium stearate. In another embodiment, the pharmaceutical composition of the present disclosure may consist of 7 to 46% by weight of Lazertinib mesylate; 50 to 87% by weight of the combination of microcrystalline cellulose and mannitol; 2 to 5% by mass of croscarmellose sodium; and 0.5 to 1.5% by weight of magnesium stearate.

Lazertinib mesylate may be a crystalline form. In one embodiment, Lazertinib mesylate may be a crystalline form having a PXRD pattern with maxima at 5.614, 12.394, 14.086, 17.143, 18.020, 19.104, 21.585, 22.131, and 22.487°2θ ± 0.2°2θ. In another embodiment, Lazertinib mesylate may be a crystalline form having a differential scanning calorimetric (DSC) thermogram with an endothermic maximum of 210 to 230°C, preferably 217±2°C. Lazertinib mesylate may have an onset of 214±2°C.

Lazertinib mesylate can be prepared by a preparation method comprising (a) mixing Lazertinib free base with a single organic solvent or a mixed solvent, followed by adding methanesulfonic acid thereto to form Lazertinib mesylate, and ( b) crystallization of Lazertinib mesylate by adding an organic solvent to the mixture in step (a).

The single organic solvent in step (a) is not particularly limited, but may be selected from the group consisting of acetone, methyl ethyl ketone, and ethyl acetate. The mixed solvent of step (a) may be a mixed solvent of water and one or more suitable organic solvents. Specifically, a mixed solvent of water and one or more organic solvents selected from acetone and methyl ethyl ketone is preferable, but is not limited thereto. A mixing ratio of water to organic solvent may be from 1:1 to 1:10 by volume and specifically from 1:4 to 1:6, but is not limited thereto. Step (a) may be carried out at a temperature of 20 to 70°C, preferably 45 to 60°C.

The crystallization in step (b) can be carried out by adding the organic solvent to the mixture obtained in step (a), stirring, cooling, and filtering the mixture, and then drying it to obtain the resulting solid. The organic solvent in step (b) can be the same or different from the organic solvent alone in step (a). Specifically, the organic solvent in step (b) may be at least one selected from the group consisting of acetone, methyl ethyl ketone, and ethyl acetate. The organic solvent from step (b) can be added in a volume of 3 mL to 20 mL per 1 g of Lazertinib free base used in step (a). Specifically, the organic solvent may be added in a volume of 5 mL to 20 mL per 1 g of Lazertinib free base used in step (a) and, more specifically, in a volume of 5 mL to 10 mL, but is not limited to these. The mixture obtained by adding the organic solvent can be cooled to a temperature of 0 to 30°C, preferably 0 to 10°C, and then dried at a temperature of 30 to 70°C to isolate the mesylate from Lazertinib.

The pharmaceutical composition of the present disclosure can be used to prevent or treat allograft rejection, graft-versus-host disease, diabetic retinopathy, choroidal angiogenesis due to age-related visual loss, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, pannus invasion of the synovial membrane in arthritis , multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic vascular disease, retinopathy of prematurity, infantile hemangioma, non-small cell lung cancer, bladder cancer, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, gastric cancer, cancer pancreatic, psoriasis, fibrosis, atherosclerosis, recurrent stenosis, autoimmune disease, allergy, respiratory disease, asthma, transplant rejection, inflammation, thrombosis, retinal duct proliferation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone disease, graft or transplant rejection of bone marrow, lupus, chronic pancreatitis, cachexia, septic shock, fibrosis and various skin diseases and disorders, central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, disorders or symptoms associated with nerve damage after brain injury or spinal cord and exon metamorphoses, acute or chronic cancer, eye disease, viral infection, heart disease, lung disease or kidney disease, and bronchitis. The pharmaceutical composition of the present disclosure can be used for the prevention or treatment of cancer, preferably acute or chronic, more preferably lung cancer, most preferably non-small cell lung cancer or cerebral metastatic non-small cell lung cancer, but not limited thereto.

Further in this document, this disclosure will be described in more detail by means of Examples and Test Examples.

In the following Examples and Test Examples, "Lazertinib" refers to N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl)acrylamide, and "Lazertinib mesylate" refers to the mesylic acid salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole- 1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

Reference Example 1: Preparation of Lazertinib Mesylate

A compound prepared in the same manner as the method disclosed in WO 2016/060443, i.e., N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2 -ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) (1,100.0 g, 1,983.2 mmol), acetone (4.4 L), and purified water (1.1 L) was placed in a reactor and heated from 45 to 55°C with stirring. Methane sulfonic acid (186.8 g, 1,943.6 mmol) was diluted in purified water (0.55 L) and then the resulting solution was added thereto while maintaining a temperature of 45°C or higher. The resulting mixture was stirred for 30 minutes or more to prepare a mixture containing N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole-1) mesylic acid salt -yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

Then, to crystallize the mesylated compound in the mixture, acetone (8.8 L) was added thereto while maintaining a temperature of 40 to 50°C. The resulting mixture was stirred for 30 minutes or more, cooled to 0 to 5°C, and then stirred for 3 hours or more. The reaction mixture was filtered under reduced pressure, the wet cake was washed with acetone (5.5 L), and then the resulting solid was dried at 55°C under vacuum to obtain 1,095.8 g of Lazertinib mesylate (yield: 84.9%).

The results of the measurement of Lazertinib mesylate obtained by 1H-NMR (400 MHz, DMSO-d6) are as follows.

1H-NMR(400MHz, DMSO-d6) δ 9.79(s, 1H), 9.35(s, 1H), 9.21(s, 1H), 8.78(s, 1H), 8.59 (d, 1H), 8.33(s, 1H), 7.77(d, 2H), 7.55(m, 3H), 7.34(d, 1H), 6.94(s, 1H) , 6.71-6.76(q, 1H), 6.28-6.31(d, 1H), 5.81-5.83(d, 1H), 4.48(s, 2H), 3 .90(s, 3H), 3.81-3.83(t, 4H), 2.86-2.88(t, 4H), 2.66(s, 6H), 2.35(s, 3H ).

As a result of the PXRD measurement of the obtained Lazertinib mesylate, a PXRD pattern with maxima at 5.614, 12.394, 14.086, 17.143, 18.020, 19.104, 21.585, 22.131, and 22.487 °2θ ± 0.2°2θ was presented (FIG. 1 ). The PXRD spectrum was measured using the Bruker D8 advance (X-ray source: CuKα, tube voltage: 40 kV / tube current: 40 mA, emission slit: 0.3, and dispersion slit: 0.3).

As a result of the measurement of Lazertinib mesylate obtained by DSC, an endothermic maximum at approximately 217°C was shown in a DSC plot (FIG. 2). DSC was measured using a Mettler Toledo DSC 1 STAR (sample container: sealed aluminum tray, 99% nitrogen conditions, and ramped up to 10°C per minute from 30°C to 300°C).

Reference Example 2: Property Evaluation and Pharmacokinetic Test of Lazertinib Mesylate

(1) Solubility test

Solubility according to pH and solubility in artificial gastric juice, artificial intestinal fluid, water and ethanol were compared to each other relative to Lazertinib mesylate and Lazertinib free base.

120 mg of Lazertinib mesylate (100 mg as Lazertinib) prepared in Reference Example 1 was added to 5 mL of a buffer solution having each pH disclosed in the following Table 1, artificial gastric juice, artificial intestinal fluid, water, or ethanol and then agitated under conditions of 37°C, water bath, and 50 rpm for 12 hours. In addition, 100 mg of Lazertinib free base (prepared in the same manner as the method described in WO 2016/060443) was tested under the same conditions. After 12 hours of stirring, the concentration of dissolved Lazertinib was measured and the solubility was compared. The results were presented in Table 1 below.

[Table 1]

Solubility (mg/mL) pH 1.2 pH 2.0 pH 3.0 pH 4.0 pH 5.0 pH 6.0 pH 7.0 Artificial gastric juice (FaSSGF) Artificial intestinal fluid (FaSSIF) Water Ethanol Free base Lazertinib 4.4 3.7 1.9 1.0 0.01 0.003 0.001 1.5 0.027 0.001 0.599 Lazertinib Mesylate 14.9 14.1 17.9 20.9 18.4 1.2 0.018 10.1 0.68 21.6 17.3

As illustrated in Table 1, Lazertinib mesylate had water solubility 20,000 times higher than that of Lazertinib free base, solubility in artificial gastric juice (FaSSGF) about 10 times higher than that of Lazertinib free base , and solubility in artificial intestinal fluid (FaSSIF) approximately 25 times higher than that of Lazertinib free base.

(2) Stability test

A stability test for Lazertinib mesylate was performed under stress conditions and accelerated conditions, and each condition was as shown in Table 2 below.

[Table 2]

Classification Stress condition Accelerated condition Temperature 60±2°C 40±2°C Humidity 75±5% (relative humidity) 75±5% (relative humidity) Container 10 mL stick vial and rubber cap Double polyethylene bag, high density polyethylene (HDPE) bottle Time of sampling At the start, after 2 weeks, and after 4 weeks At the start, after 1 month, after 3 months, and after 6 months

(2-1) Stability test under stress conditions

Stability for Lazertinib mesylate was tested under the stress conditions described in Table 2 above, and the results were illustrated in FIG. 3 and Tables 3 and 4 below. The measurement conditions for PXRD and DSC are the same as described in Reference Example 1.

[Table 3]

PXRD pattern DSC onset (°C) Appearance (color) Start 2 weeks 4 weeks Start 2 weeks 4 weeks Start 2 weeks 4 weeks - Same pattern Same pattern 214 214 214 White White White

In addition, the high performance liquid chromatography (HPLC) measured results were shown in Table 4 below, and the measurement conditions were as follows. Mobile phase buffer: 250 mM ammonium acetate in water (Mobile phase A: buffer/water/acetonitrile, Mobile phase B: acetonitrile, column: Xbridge BEH C18 XP)

[Table 4]

Purity (%) Content (%) Water content (%) Start 2 weeks 4 weeks Variation Start 2 weeks 4 weeks Variation Start 2 weeks 4 weeks Variation 99.2 99.3 99.3 +0.1 98.8 97.7 98.9 +0.1 2.48 2.71 2.70 +0.22

(2-2) Stability test under accelerated conditions

Stability for Lazertinib mesylate was tested under the accelerated conditions described in Table 2 above, and the results were illustrated in FIG. 4 and Tables 5 and 6 below. The measurement conditions for PXRD and DSC are the same as described in Example 1.

[Table 5]

PXRD pattern DSC onset (°C) Appearance (color) Start 1 month 3 months 6 months Start 1 month 3 months 6 months Start 1 month 3 months 6 months - Same pattern Same pattern Same pattern 214 214 214 214 White White White White

In addition, the high performance liquid chromatography (HPLC) measured results were shown in Table 6 below, and the measurement conditions were the same as disclosed in (2-2).

[Table 6]

Purity (%) Content (%) Water content (%) Start 1 month 3 months 6 months Variation Start 1 month 3 months 6 months Variation Start 1 month 3 months 6 months Variation 99.2 99.3 99.3 99.3 + 0.1 98.8 98.9 98.9 99.1 +0.3 2.48 2.73 3.19 3.01 +0.53

From the results of the stability test, Lazertinib mesylate showed a slight change in purity and water content between the starting point and the end time of the stability test, showed no change in the PXRD pattern, and showed no change in the aspect observed by color, and thus its stability was excellent.

(3) Comparative Pharmacokinetic Test for Lazertinib Mesylate and Lazertinib Free Base in Normal Rats and Esomeprazole Treated Rats

For Lazertinib mesylate and Lazertinib free base, the pharmacokinetics were compared to each other in normal rats and in rats treated with esomeprazole which was a proton pump inhibitor, respectively. Specifically, in normal rats and rats treated with esomeprazole, the maximum blood concentrations (Cmax) and the areas under the blood concentration curve (AUClast) were compared with each other, respectively, to evaluate drug absorption in animals.

To perform the comparative pharmacokinetic test, approximately 250 g of 8-week-old male rats (SD rats) were selected as test animals, and Lazertinib mesylate and Lazertinib free base were suspended in 0.5% methyl cellulose, and then administered orally to normal rats at a dose of 30 mg/5 mL/kg.

In addition, esomeprazole (esomeprazole magnesium dihydrate, manufactured by Sigma-Aldrich) was administered intravenously to approximately 250 g of 8-week-old male rats at a dose of 5 mg/2 mL/kg for 3 days, and then Lazertinib mesylate and Lazertinib free base were administered orally at the same dose (30 mg/5 mL/kg) as the dose administered to normal rats. The results (maximum blood concentration and area under the blood concentration curve) of the comparative pharmacokinetic test obtained from them were presented in Table 7 and FIGURES 5 and 6.

[Table 7]

Pharmacokinetic parameter Normal rat Esomeprazole-treated rat Lazertinib mesylate Lazertinib free base Lazertinib mesylate Lazertinib free base Maximum blood concentration (Cmax, ng/mL) 815.6 725.7 427.5 223.0 Area under the blood concentration curve (AUCultim, ng.hours/mL) 8139.0 7293.6 5210.9 2636.7

As shown in the results above, for Lazertinib free base, peak blood concentration and area under the blood concentration curve were observed to be 11.0% and 10.4% lower than Lazertinib mesylate in normal rats , respectively, and peak blood concentration and area under the blood concentration curve were observed to be 47.8% and 49.4% lower than Lazertinib mesylate in esomeprazole-treated rats, respectively. That is, Lazertinib free base can be seen to have a lower body exposure than Lazertinib mesylate.

In addition, in esomeprazole-treated rats, for Lazertinib mesylate, the peak blood concentration and the area under the blood concentration curve were reduced by 47.6% and 36.0% compared to normal rats, respectively. However, in the case of Lazertinib free base, the peak blood concentration and area under the blood concentration curve were reduced by 69.3% and 63.8% compared to normal rats, respectively. From these results, it can be seen that Lazertinib mesylate exhibits less change in pharmacokinetics in accordance with esomeprazole administration than Lazertinib free base, thereby maintaining a high blood concentration in rats.

(4) Pharmacokinetic test for Lazertinib mesylate and Lazertinib free base in beagle dogs

To perform a comparative pharmacokinetic test, approximately 10 kg male Beagle dogs aged 15 to 17 months were selected as test animals, and Lazertinib mesylate and Lazertinib free base were suspended in 0.5% methyl cellulose, and then administered orally to beagle dogs at a dose of 5 mg/2 mL/kg. The results (maximum blood concentration and area under the blood concentration curve) of the comparative pharmacokinetic test obtained from them were presented in Table 8 and FIG. 7.

[Table 8]

Lazertinib mesylate Lazertinib free base Peak blood concentration (Cmax, ng/mL) 134.7 80.7 Area under the blood concentration curve (AUCultim, ng.hours/mL) 811.5 379.1

As shown in the results above, as a result tested for beagle dogs, it was observed that Lazertinib free base showed peak blood concentration and area under the blood concentration curve that were 40.1% and 50.4% higher lower than Lazertinib mesylate, respectively. From these results, it can be seen that Lazertinib mesylate maintains a higher blood concentration than Lazertinib free base in beagle dogs.

As such, Lazertinib mesylate is excellent in solubility and bioavailability compared to Lazertinib free base. Lazertinib mesylate has improved stability, solubility and bioavailability, and is excellent in terms of its high purity.

Examples 1 to 8. Tablet preparation

According to the ingredients and contents of Table 9 below, a tablet containing Lazertinib mesylate was prepared. The content in Table 9 represents mg per unit tablet. Specifically, an active ingredient, an additive, and a disintegrant were mixed using a blender, and then further mixed with a lubricant. The resulting mixture was compressed using a tablet press machine (XP1 from Corsch Corporation) to prepare a tablet.

[Table 9]

Ingredient Examples (mg/tablet) 1 2 3 4 5 6 7 8 Active Ingredient Lazertinib Mesylate (as Lazertinib) 11.73 (10.00) 11.73 (10.00) 23.47 (20.00) 23. 47 (20.00) 46.93 (40.00) 46.93 (40.00) 93.86 (80.00) 93.86 (80.00) Additive Microcrystalline Cellulose 65.27 42.55 67.53 35.38 65.07 32.52 67.14 33.29 D-mannitol 65.00 87.72 66.00 98.15 65.00 97.55 66.00 99.85 Disintegrating agent sodium croscarmellose 6, 00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 magnesium stearate lubricant 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Total table 150.00 150.00 165.00 165.00 185.00 185.00 235.00 235.00

Examples 9 to 13. Tablet preparation

According to the ingredients and contents of Table 10 below, a tablet containing Lazertinib mesylate was prepared. The content in Table 10 represents mg per unit tablet. Specifically, an active ingredient, an additive, and a disintegrant were mixed using a blender, and then further mixed with a lubricant. The resulting mixture was compressed using a tablet press machine (XP1 from Corsch Corporation) to prepare a tablet.

[Table 10]

Ingredient Examples (mg/tablet) 9 10 11 12 13 Active Ingredient Lazertinib Mesylate (as Lazertinib) 117.33 (100.00) 140.79 (120.00) 187.72 (160.00) 281.58 (240 .00) 375.44 (320.00) Additive Microcrystalline cellulose 67.67 100.71 134.28 201.42 268.56 D-mannitol 67.00 99.00 132.00 198.00 264.00 Disintegrating agent croscarmellose sodium 6.00 9.00 12.00 18.00 24.00 Lubricant magnesium stearate 2.00 3.00 4.00 6.00 8.00 Total mass 260.00 352.50 470.00 705, 00 940.00

Comparative Examples 1 to 6. Tablet Preparation

According to the ingredients and contents of Table 11 below, a tablet containing Lazertinib mesylate was prepared. The content in Table 11 represents mg per unit tablet. Specifically, an active ingredient, an additive, and a disintegrant were mixed using a blender, and then further mixed with a lubricant. The resulting mixture was compressed using a tablet press machine (XP1 from Corsch Corporation) to prepare a tablet.

[Table 11]

Ingredient Comparative examples (mg/tablet) 1 2 3 4 5 6 Active ingredient Lazertinib mesylate (as Lazertinib) 46.93 (40.00) 93.86 (80.00) 11.73 (10.00) 11.73 (10.00) 93.86 (80.00) 93.86 (80.00) Additive Microcrystalline cellulose 35.07 36.14 - - - - lactose hydrate 95.00 97.00 - - - - Microcrystalline cellulose - - 98.00 - 67.14 67.14 D-mannitol - - 32.27 - 66.00 66.00 Microshellac* - - - 130.27 - - Disintegrating agent croscarmellose sodium 6.00 6.00 6.00 6.00 - - Crospovidone - - - - 6.00 - sodium starch glycolate - - - - - 6.00 Magnesium stearate lubricant 2.00 2.00 2.00 2.00 2.00 2.00 Table total 185.00 235.00 150.00 150.00 235.00 235.00 * Microshellac: Additive consisting of 73 to 77% lactose hydrate and 23 to 27% microcrystalline cellulose

Test example 1. Compatibility test with Lazertinib mesylate and /lubricant/rheological agent

A mixture (Amestec A) of 1,000 mg Lazertinib mesylate and 1,000 mg magnesium stearate, a mixture (Amestec B) of 1,000 mg Lazertinib mesylate and 1,000 mg sodium stearyl fumarate, and a mixture (Amestec C) of 1,000 mg of Lazertinib mesylate and 1,000 mg of colloidal silicon dioxide (ie, Aerosil 200) were compressed by applying the pressure of 1 kN, respectively, to prepare a compression material. The maximum unknown impurity and total impurity contents of the mixture before compression and the maximum unknown impurity and total impurity contents of the resulting compression material were measured, respectively. And also, the obtained compression material was put into a glass bottle made of HDPE and stored under severe conditions (60±2°C, 75±5% RH) for 1 week, and then the contents of maximum unknown impurity and total impurity. The impurity content was analyzed by ultra-performance liquid chromatography (UPLC) under the following conditions.

<ULPC Conditions>

• Column: ACQUITY UPLC(R) HSS T3, 1.8 µparticle size, 2.1 × 100 mm • Mobile phase A: Buffer/Acetonitrile = 95/5 (v/v %) • Mobile phase B: Buffer/Acetonitrile = 5/95 (v/v %)

* Buffer: 20 mM ammonium bicarbonate (adjusted to pH 7.0 using formic acid)

• Flow rate: 0.4 mL/min • Column temperature: 40°C • Wavelength: 285 nm As such, the results of performing the compatibility test are shown in Table 12 below.

[Table 12]

Maximum unknown impurity (%) Total impurity (%) Initial 1 week Initial 1 week Before compression After compression Before compression After compression Mix A 0.14 0.13 0.13 0.4 0.5 0.4 Mix B 0 .14 0.30 0.29 0.4 0.8 0.7 Mixture C 0.13 0.14 0.19 0.4 0.5 0.5

As seen from the above results in Table 12, in the mixture of Lazertinib mesylate and magnesium stearate, no significant increase in the amount of impurity was observed either before or after compression and during storage for 1 week under severe conditions. However, in the mixture of Lazertinib mesylate and sodium stearyl fumarate, a significant increase in the amount of impurity was shown in the compression process. In addition, in the mixture of Lazertinib mesylate and colloidal silicon dioxide, a significant increase in the amount of impurity was shown for 1 week under severe conditions. Accordingly, it can be seen that magnesium stearate in particular has excellent compatibility with respect to Lazertinib mesylate.

Test example 2. Tablet dissolution test (1).

A dissolution test was performed according to the following conditions with respect to the tablets of Example 5 and Comparative Example 1, and each sample was analyzed by HPLC.

<Dissolution test conditions>

Dissolution test solution:

1) solution with pH 1.2 - the first solution of the disintegration test of the Korean Pharmacopoeia

2) pH 4.0 solution - acetate buffer solution (mixture of 0.05 mol/L acetic acid solution and 0.05 mol/L sodium acetate solution (41:9, v/v), and adjusted to pH 4.0)

Amount of dissolution test solution: 900 mL

Temperature of the dissolution test solution: 37±0.5°C

Dissolution Test Method: Korean Pharmacopoeia Second Dissolution Test Method (50 rpm)

Time of sampling:

1) solution with pH 1.2 - 5 minutes, 10 minutes, 15 minutes, 30 minutes

2) solution with pH 4.0 - 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes

<HPLC conditions>

• Column: Luna C18 (2), particle size 5 µm, 4.6 ×50 mm • Mobile phase: Buffer/Acetonitrile = 40/60 (v/v %)

* Buffer: 20 mM ammonium bicarbonate (adjusted to pH 7.2 using formic acid)

• Flow rate: 2.0 mL/min • Column temperature: 50°C • Wavelength: 298 nm The results of the dissolution tests performed as above are shown in FIGURES 8 through 9. In addition, an enlarged dissolution pattern of FIG. . 9 is shown in FIG. 10. As illustrated in FIGURES 8 through 10, the tablet of Example 5 had no significant difference between the dissolution rate at pH 1.2 indicating a pre-meal state and the dissolution rate at pH 4.0 indicating a state after a meal. In contrast, in the tablet of Comparative Example 1, the dissolution rate at pH 4.0 was significantly reduced compared to the dissolution rate at pH 1.2. Thus, the tablet of the present disclosure can minimize deviations in dissolution according to changes in pH according to food or drugs (eg, antacids, etc.).

Test example 3. Tablet dissolution test (2).

A dissolution test was performed according to the following conditions with respect to the tablets of Examples 1 and 2 and Comparative Example 3, and each sample was analyzed by HPLC. The HPLC analysis conditions are the same as in Test Example 2.

<Conditions of the dissolution test>

Dissolution test solution: pH 4.0 solution - acetate buffer solution (mixture of 0.05 mol/L acetic acid solution and 0.05 mol/L sodium acetate solution (41:9, v/v), and adjusted to pH 4.0)

Amount of dissolution test solution: 900 mL

Temperature of the dissolution test solution: 37±0.5°C

Dissolution test method: Second Korean Pharmacopoeia dissolution test method (50 rpm)

Sampling time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes

The results of the dissolution tests performed as above are shown in FIG. 11. As illustrated in FIG. 11, in the case of using a larger amount (approximately 3 times) of microcrystalline cellulose than mannitol, the dissolution rate at pH 4.0 was significantly reduced. In contrast, it can be seen that the tablet of the present disclosure exhibits a uniform dissolution rate.

Test example 4. Tablet dissolution test (3).

A dissolution test was performed according to the following conditions with respect to the tablets of Example 7 and Comparative Examples 5 and 6, and each sample was analyzed by HPLC. The HPLC analysis conditions are the same as in Test Example 2.

<Conditions of the dissolution test>

Dissolution test solution:

1) Acidic phase - 0.1N hydrochloric acid solution 750 mL

2) Buffer phase - 1) acid phase 750 mL + 0.2 M sodium triphosphate solution 250 mL

Temperature of the dissolution test solution: 37±0.5°C

Dissolution Test Method: Korean Pharmacopoeia Second Dissolution Test Method (50 rpm)

(After performing a dissolution test for 30 minutes in dissolution solution (750 mL) of an acid phase, 250 mL of a 0.2 M sodium triphosphate solution was added to become a dissolution solution ( 1,000 mL) of the buffer phase, and then additional dissolution tests were performed for 60 minutes).

Time of sampling:

1) Acid phase - 5 minutes, 10 minutes, 15 minutes, 30 minutes

2) Buffer phase - 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes

The results of the dissolution tests performed as above are shown in FIG. 12. From the results in FIG. 12, it can be observed that in the tablet obtained using croscarmellose sodium as a disintegrating agent, the precipitation of a drug in the buffer phase is the most delayed.

Test example 5. Stability test

The tablets of Example 1 and Comparative Example 4 were placed in an aluminum bag and stored for 2 weeks under severe conditions (60±2°C, 75±5% RH), and then the maximum unknown impurity contents were measured and respectively of total impurity. The impurity content was analyzed by ultra-performance liquid chromatography (UPLC). The UPLC analysis conditions are the same as in Test Example 1.

As such, the results of performing the stability test are shown in Table 13 below.

[Table 13]

Sample Maximum Unknown Impurity (%) Total Impurity (%) Initial 1 week 2 weeks Initial 1 week 2 weeks Example 1 0.01 0.04 0.05 0.4 0.3 0.4 Comparative Example 4 0.01 0, 10 0.10 0.4 0.4 0.4

As seen from the results in Table 13 above, in the tablet obtained according to the present disclosure, no significant increase in impurity was observed. However, in the tablet of Comparative Example 4, the unknown impurity increased significantly.

Test example 6. Pharmacokinetic test

Compared to the tablets of Example 7 and Comparative Example 2, the pharmacokinetics in beagle dogs were compared with each other, respectively. The tablets (composition containing 80 mg as YH25448) prepared in Example 7 and Comparative Example 2 were orally administered to a prefasted beagle dog (under fasted conditions) for 14 hours on the day before the test, and then a pharmacokinetic test.

A blood concentration profile obtained by performing the pharmacokinetic test as above is shown in FIG. 13. In addition, the pharmacokinetic parameters obtained from the blood concentration profile, that is, a maximum blood concentration (Cmax) and an area under the blood concentration curve (AUCultim) are presented in Table 14 below.

[Table 14]

Example 7 Comparative example 2 Maximum blood concentration (Cmax, ng/ml) 2353.0 3426.0 Area under the blood concentration curve (AUCultim, ng.ores/mL) 19657.8 17080.4

According to the results in Table 14 and FIG. 13, it can be seen that the tablet obtained according to the present disclosure has a high AUC value and excellent bioavailability. In addition, the maximum blood concentration can be lowered, being able therefore to reduce the risk of toxicity.

Claims (14)

1. A pharmaceutical composition for oral administration comprising: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy -2-morpholinophenyl)acrylamide (Lazertinib) or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent. 2. The pharmaceutical composition according to claim 1, wherein a mass ratio of microcrystalline cellulose to mannitol is in a range from 1:0.5 to 1:3. 3. The pharmaceutical composition according to claim 1, wherein a mass ratio of microcrystalline cellulose to mannitol is in a range from 1:0.9 to 1:3. The pharmaceutical composition according to claim 1, wherein a mass ratio of microcrystalline cellulose to mannitol is in a range from 1:0.9 to 1:1.5. 5. The pharmaceutical composition according to claim 1, further comprising: croscarmellose sodium as a disintegrating agent. 6. The pharmaceutical composition according to claim 5, wherein croscarmellose sodium is present in a range of 2 to 5% by weight, based on the total weight of the composition. 7. The pharmaceutical composition according to claim 1, further comprising: magnesium stearate as a lubricant. 8. The pharmaceutical composition according to claim 1, comprising: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4 -methoxy-2-morpholinophenyl)acrylamide or its pharmaceutically acceptable salt as an active ingredient; a combination of microcrystalline cellulose and mannitol as a diluent; croscarmellose sodium as a disintegrating agent; and magnesium stearate as a lubricant. The pharmaceutical composition according to any one of claims 1 to 8, wherein the active ingredient is mesylated by N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide. 10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition consists of 5 to 54% by weight of mesylate of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide; 45 to 87% by weight of the combination of microcrystalline cellulose and mannitol; 0.5 to 10% by mass of croscarmellose sodium; and 0.4 to 2% by weight of magnesium stearate. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition consists of 7 to 46% by weight of mesylate of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide; 50 to 87% by weight of the combination of microcrystalline cellulose and mannitol; 2 to 5% by mass of croscarmellose sodium; and 0.5 to 1.5% by weight of magnesium stearate. 12. The pharmaceutical composition according to claim 9, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino) mesylate -4-methoxy-2-morpholinophenyl)acrylamide is a crystalline form having a PXRD pattern with maxima at 5.614, 12.394, 14.086, 17.143, 18.020, 19.104, 21.585, 22.131, and 22.487°2θ ± 0.2°2θ. 13. The pharmaceutical composition according to claim 9, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino) mesylate -4-Methoxy-2-morpholinophenyl)acrylamide is a crystalline form having a differential scanning calorimetric (DSC) thermogram with an endothermic maximum from 210 to 230°C. 14. The pharmaceutical composition according to claim 13, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino) mesylate -4-Methoxy-2-morpholinophenyl)acrylamide is a crystalline form having a differential scanning calorimetric (DSC) thermogram with an endothermic maximum at 217±2°C.